PDE3 Inhibition Reduces Epithelial Mast Cell Numbers in Allergic Airway Inflammation and Attenuates Degranulation of Basophils and Mast Cells

Epithelial mast cells are generally present in the airways of patients with allergic asthma that are inadequately controlled. Airway mast cells (MCs) are critically involved in allergic airway inflammation and contribute directly to the main symptoms of allergic patients. Phosphodiesterase 3 (PDE3) tailors signaling of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are critical intracellular second messenger molecules in various signaling pathways. This paper investigates the pathophysiological role and disease-modifying effects of PDE3 in mouse bone marrow-derived MCs (bmMCs), human LAD2- and HMC1 mast cell lines, human blood basophils, and peripheral blood-derived primary human MCs (HuMCs). In a chronic house dust mite (HDM)-driven allergic airway inflammation mouse model, we observed that PDE3 deficiency or PDE3 inhibition (PDE3i) therapy reduced the numbers of epithelial MCs, when compared to control mice. Mouse bone marrow-derived MCs (bmMCs) and the human HMC1 and LAD2 cell lines predominantly expressed PDE3B and PDE4A. BmMCs from Pde3−/− mice showed reduced loss of the degranulation marker CD107b compared with wild-type BmMCs, when stimulated in an immunoglobulin E (IgE)-dependent manner. Following both IgE-mediated and substance P-mediated activation, PDE3i-pretreated basophils, LAD2 cells, and HuMCs, showed less degranulation than diluent controls, as measured by surface CD63 expression. MCs lacking PDE3 or treated with the PDE3i enoximone exhibited a lower calcium flux upon stimulation with ionomycine. In conclusion PDE3 plays a critical role in basophil and mast cell degranulation and therefore its inhibition may be a treatment option in allergic disease

Stereotactic cyst aspiration directly followed by Gamma Knife radiosurgery for large cystic brain metastases

Background: Gamma Knife radiosurgery (GKRS) has been proven to be a successful primary treatment for metastatic brain tumors (BM). BM can come in cystic lesions and are often too large for GKRS. An alternative approach to treat cystic BM is stereotactic cyst aspiration (SCA) for volume reduction, making it suitable for GKRS afterwards. Objective: Our objective is evaluation of volumetric reduction after SCA, tumor control, and complications after SCA directly followed by GKRS. Methods: We performed a retrospective analysis of all patients who underwent SCA directly followed by GKRS at the Gamma Knife Center of the Elisabeth-Tweesteden Hospital in Tilburg between 2002 and 2015. In total, 54 patients had undergone this combined approach. Two patients were excluded because of prior intracranial treatment. The other 52 patients were included for analysis. Results: SCA resulted in a mean volumetric reduction of 56.5% (range 5.50–87.00%). In 83.6% of the tumors (46 tumors), SCA led to sufficient volumetric reduction making GKRS possible. The overall local tumor control (OLTC) of the aspirated lesions post-GKRS was 60.9% (28 out of 46 tumors). Median progression-free survival (PFS) and overall survival (OS) for all patients were 3 (range 5 days–14 months) and 12 months (range 5 days–58 months), respectively. Leptomeningeal disease was reported in 5 (9.6%) cases. Conclusion: SCA directly followed by GKRS is an effective and time-efficient treatment for large cystic BM in selected patients in which surgery is contraindicated and those with deeply located lesions

Gamma knife radiosurgery for recurrent gliomas

Objective: In recent years, gamma knife radiosurgery (GKRS) has become increasingly more popular as a salvage treatment modality for patients diagnosed with recurrent gliomas. The goal of GKRS for recurrent glioma patients is to improve survival rates with minimal burden for these patients. The emphasis of this report is on local tumor control (TC), clinical outcome and survival analysis. Methods: We performed a retrospective analysis of prospectively collected data of all patients who underwent GKRS for gliomas at the Gamma Knife Center Tilburg between 23-09-2002 and 21-05-2015. In total, 94 patients with glioma were treated with GKRS. Two patients were excluded because GKRS was used as a first stage treatment. The other 92 patients were included for analysis. Results: TC was 37% for all tumors (TC was 50% in LGGs and 27% in HGGs). Local progression (LP) was 46% for all tumors (LP was 31% in LGGs and 58% in HGGs). New distant lesions were seen in 18% of all patients (in 5% of LGG patients and 31% of HGG patients). Median progression-free and overall survival (PFS and OS) for all patients were 10.5 and 34.4 months, respectively. Median PFS was 50.1 and 5.7 months for low and high grade tumors, respectively. Median OS was 86.6 and 12.8 months for low and high grade tumors, respectively. No serious adverse events were noted post-GKRS. Conclusion: GKRS can safely be used as salvage treatment for recurrent glioma and seems to improve survival rates in (high grade) glioma patients with minimal burden

Diepe hersenstimulatie bij patienten met een minimale bewustzijnstoestand: huidige stand van zaken.

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Radiotherapy for partially resected spinal ependymomas: a retrospective study of 60 cases.

Item does not contain fulltextEpendymomas (Es) and myxopapillary ependymomas (mpEs) are the most common primary tumours of the spinal cord. Recurrence-free survival depends on local control of the tumour. The value of additional radiotherapy (RT) is still a matter of debate. The aim of this retrospective study was to analyse radiotherapy, surgery and the preoperative state with regard to recurrence rate and long-term neurological outcome. Sixty patients with spinal Es (40) and spinal mpEs (20) were included. According to local policy, 14 patients who underwent total resection and 20 patients with incomplete resection were irradiated postoperatively. Total resection was achieved in 34 of the 60 tumours. Preoperative state and long-term outcome was assessed according to a previously published scale. When postoperative RT was applied after partial resection, only 3 of 11 Es and 1 of 9 mpEs recurred. All partially resected non-radiated Es (n=3) and 2 of the 3 partially resected non-radiated mpEs recurred. There was no recurrence after total resection. Only one of 6 patients with disseminated mpEs had clinical symptoms caused by the disseminated tumour. Long-term neurological outcome was related to preoperative conditions with no difference between partially and totally resected tumours. Our study shows that RT is only beneficial for partially resected Es and mpEs. Local recurrence-free survival of spinal Es and mpEs is obtained by total resection. Long-term neurological outcome is related to preoperative conditions. Seeding is seen in mpEs and does not cause clinical symptoms in most of the patients

Radiotherapy for partially resected spinal ependymomas: a retrospective study of 60 cases.

Ependymomas (Es) and myxopapillary ependymomas (mpEs) are the most common primary tumours of the spinal cord. Recurrence-free survival depends on local control of the tumour. The value of additional radiotherapy (RT) is still a matter of debate. The aim of this retrospective study was to analyse radiotherapy, surgery and the preoperative state with regard to recurrence rate and long-term neurological outcome. Sixty patients with spinal Es (40) and spinal mpEs (20) were included. According to local policy, 14 patients who underwent total resection and 20 patients with incomplete resection were irradiated postoperatively. Total resection was achieved in 34 of the 60 tumours. Preoperative state and long-term outcome was assessed according to a previously published scale. When postoperative RT was applied after partial resection, only 3 of 11 Es and 1 of 9 mpEs recurred. All partially resected non-radiated Es (n=3) and 2 of the 3 partially resected non-radiated mpEs recurred. There was no recurrence after total resection. Only one of 6 patients with disseminated mpEs had clinical symptoms caused by the disseminated tumour. Long-term neurological outcome was related to preoperative conditions with no difference between partially and totally resected tumours. Our study shows that RT is only beneficial for partially resected Es and mpEs. Local recurrence-free survival of spinal Es and mpEs is obtained by total resection. Long-term neurological outcome is related to preoperative conditions. Seeding is seen in mpEs and does not cause clinical symptoms in most of the patients

Surgery, radiotherapy or a combined modality for jugulotympanic paraganglioma of Fisch class C and D

Contains fulltext : 200416.pdf (publisher's version ) (Closed access)OBJECTIVES: To identify the risks associated with surgery, radiotherapy or a combined treatment approach for Fisch class C and D jugulotympanic paraganglioma, in order to develop an individualised approach for each patient depending on Fisch class, age, mutation presence, tumour size growth rate and presenting symptoms. DESIGN: A retrospective multicenter cohort study with all patient records of patients with a head and neck paraganglioma in the Radboudumc, Nijmegen and the St. Elisabeth Hospital, Tilburg, the Netherlands. MAIN OUTCOME MEASURES: Local control, cranial nerve damage, complications, function recovery. RESULTS: We found highest local control rates after tumour debulking with postoperative radiotherapy in case of residual tumour growth, referred to as the combined treatment group, (100%; n = 19), which was significantly higher than the surgical group (82%; n = 17; P = 0.00), but did not differ from the radiotherapy group (90%; n = 29). There were significantly less complications in the radiotherapy group, when compared to surgery (63 vs 27%; P = 0.002) and the combined group (44 vs 27%; P = 0.016). Furthermore,: using a logistic regression model, we found that pretreatment tumour growth was a negative predictor for post-treatment cranial nerve function recovery (OR = 50.178, P = 0.001), reducing the chance of symptom recovery (67.3% vs 35.7%) post-treatment. CONCLUSIONS: Radiotherapy should be the treatment of choice for the elderly. For younger patients, tumour debulking should be considered, with potential radiotherapy in case of residual tumour growth